The focus of our investigations for the past eighteen years of support on this NIH grant has been the determination of the primary structure of immunoglobulin variable regions, especially heavy chain variable regions and the relationship of these structures to the antibody combining sites and the idiotypic determinants. To this end, we initially engaged in amino acid sequence analysis of randomly chosen human myeloma proteins without known antibody activity. We next turned to the sequence analysis of human immunoglobulin heavy chain variable regions with shared idiotypic determinants and similar antigen binding specificities and through these studies proposed the relationship between the combining specificity, the hypervariable regions, and the idiotypic determinants. Within the last decade, we focused on the arsonate system in A/J mice as a means of approaching similar problems in a defined inbred strain. The present proposal is directed toward further analysis of variable regions of immunoglobulin heavy and light polypeptide chains derived from hybridoma antibodies of the A/J and Balb/c strains. These antibodies have been or will be rigorously characterized both for binding specificity, affinity,and in a series of idiotypic (serologic) assays. The overall goal of the studies is to provide a precise molecular basis for both the antigen binding function and the idiotypic specificity of a related set of antibody molecules. During the last three years, technology has advanced such that many of the analyses are done by recombinant DNA techniques although the primary focus continues to be amino acid sequence analysis.